Mounting evidence points towards inflammation as an important factor in Alzheimer's disease (AD) pathogenesis. In this study, we investigated the relationship between a key marker of inflammation - glycoprotein acetyls (GlycA) - in blood and cognitive and brain structural changes in over 1500 participants enrolled into the Alzheimer's Disease Neuroimaging Initiative. We evaluated those associations cross-sectionally at baseline, followed by an evaluation of whether baseline GlycA can inform about future disease progression. Our results support the following findings: 1) GlycA is elevated in participants diagnosed with AD compared to cognitively normal participants; 2) GlycA level correlates negatively with regional brain volumes in females diagnosed with late mild cognitive impairment (LMCI) or AD; 3) baseline GlycA level is associated with executive function decline at 3-9 year follow-up in both male and female participants diagnosed with LMCI at baseline; and 4) baseline GlycA is associated with decline in entorhinal cortex volume at years 2, 4 and 6-8 of follow-up in both male and female participants diagnosed with LMCI at baseline. In conclusion, peripheral inflammation was found to be positively associated with AD diagnosis and future decline in cognition and regional brain volumes. However, we note that the cross-sectional relationship between peripheral inflammation and AD-related brain atrophy is specific to sex and diagnostic status. Our findings point to peripheral inflammation as a risk factor in AD development, which enables the identification of potential markers and therapeutic intervention for participants who are at risk.

Dr. Rima Kaddurah-Daouk and Dr. Matthias Arnold participated in the invention of several patents on applying metabolomics to diagnose and treat CNS diseases. Dr. Kaddurah-Daouk holds equity in Metabolon Inc., Chymia LLC and PsyProtix, which were not involved in the current study. Dr. Arnold holds equity in Chymia LLC and IP in PsyProtix. All other authors declare that they have no competing interests.

Dr. Kamil Borkowski is funded by the National Institutes of Health grant P30AG072972. Dr. Kwangsik Nho is funded by grants U01 AG072177, R01 LM012535, and U19AG074879. The Alzheimer's Disease Metabolomics Consortium (ADMC) is funded wholly or in part by the following National Institute on Aging grants and supplements, which are components of the Accelerating Medicines Partnership for AD (AMP-AD) and/or Molecular Mechanisms of the Vascular Etiology of AD (M2OVE-AD): NIA R01AG046171, RF1AG051550, RF1AG057452, R01AG059093, RF1AG058942, U01AG061359, U19AG063744, 3U19AG063744-04S1, 1R01AG081322, and FNIH: #DAOU16AMPA awarded to Dr. Rima Kaddurah-Daouk at Duke University in partnership with a large number of academic institutions. Dr. John W. Newman was supported by USDA Project 2032-51530-025-00D. The USDA is an equal opportunity provider and employer. Dr. Peter J. Meikle is supported by an Investigator grant (2009965) from the National Health and Medical Research Council of Australia. This work was supported by the Victorian Government's Operational Infrastructure Support Program. Data collection and sharing for this project was supported by the Alzheimer's Disease Neuroimaging Initiative (ADNI) with National Institutes of Health Grant U01 AG024904 and DOD ADNI with Department of Defense award number W81XWH-12-2-0012. ADNI is funded by the following entities: the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd. and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. ADNI clinical sites in Canada were supported by the Canadian Institutes of Health Research. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California.

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Data used in preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu).

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